DNA methylome analysis in Burkitt and follicular lymphomas identifies differentially methylated regions linked to somatic mutation and transcriptional control

Although Burkitt lymphomas and follicular lymphomas both have features of germinal center B cells, they are biologically and clinically quite distinct. Here we performed whole-genome bisulfite, genome and transcriptome sequencing in 13 IG-MYC translocation-positive Burkitt lymphoma, nine BCL2 translocation-positive follicular lymphoma and four normal germinal center B cell samples. Comparison of Burkitt and follicular lymphoma samples showed differential methylation of intragenic regions that strongly correlated with expression of associated genes, for example, genes active in germinal center dark-zone and light-zone B cells. Integrative pathway analyses of regions differentially methylated in Burkitt and follicular lymphomas implicated DNA methylation as cooperating with somatic mutation of sphingosine phosphate signaling, as well as the TCF3-ID3 and SWI/SNF complexes, in a large fraction of Burkitt lymphomas. Taken together, our results demonstrate a tight connection between somatic mutation, DNA methylation and transcriptional control in key B cell pathways deregulated differentially in Burkitt lymphoma and other germinal center B cell lymphomas

Genomic and transcriptomic changes complement each other in the pathogenesis of sporadic Burkitt lymphoma

Burkitt lymphoma (BL) is the most common B-cell lymphoma in children. Within the International Cancer Genome Consortium (ICGC), we performed whole genome and transcriptome sequencing of 39 sporadic BL. Here, we unravel interaction of structural, mutational, and transcriptional changes, which contribute to MYC oncogene dysregulation together with the pathognomonic IG-MYC translocation. Moreover, by mapping IGH translocation breakpoints, we provide evidence that the precursor of at least a subset of BL is a B-cell poised to express IGHA. We describe the landscape of mutations, structural variants, and mutational processes, and identified a series of driver genes in the pathogenesis of BL, which can be targeted by various mechanisms, including IG-non MYC translocations, germline and somatic mutations, fusion transcripts, and alternative splicing

MicroRNA-21 targets tumor suppressor genes ANP32A and SMARCA4

MicroRNA-21 (miR-21) is a key regulator of oncogenic processes. It is significantly elevated in the majority of human tumors and functionally linked to cellular proliferation, survival and migration. In this study, we used two experimental-based strategies to search for novel miR-21 targets. On the one hand, we performed a proteomic approach using two-dimensional differential gel electrophoresis (2D-DIGE) to identify proteins suppressed upon enhanced miR-21 expression in LNCaP human prostate carcinoma cells. The tumor suppressor acidic nuclear phosphoprotein 32 family, member A (ANP32A) (alias pp32 or LANP) emerged as the most strongly downregulated protein. On the other hand, we applied a mathematical approach to select correlated gene sets that are negatively correlated with primary-miR-21 (pri-miR-21) expression in published transcriptome data from 114 B-cell lymphoma cases. Among these candidates, we found tumor suppressor SMARCA4 (alias BRG1) together with the already validated miR-21 target, PDCD4. ANP32A and SMARCA4, which are both involved in chromatin remodeling processes, were confirmed as direct miR-21 targets by immunoblot analysis and reporter gene assays. Furthermore, knock down of ANP32A mimicked the effect of enforced miR-21 expression by enhancing LNCaP cell viability, whereas overexpression of ANP32A in the presence of high miR-21 levels abrogated the miR-21-mediated effect. In A172 glioblastoma cells, enhanced ANP32A expression compensated for the effects of anti-miR-21 treatment on cell viability and apoptosis. In addition, miR-21 expression clearly increased the invasiveness of LNCaP cells, an effect also seen in part upon downregulation of ANP32A. In conclusion, these results suggest that downregulation of ANP32A contributes to the oncogenic function of miR-21

Chapter 14: A Memorable Student and Advice to Students/Professionals

In this chapter, Dr. Arlinghaus reflects on his career at MD Anderson, noting that he is very pleased with the people he has trained.He recalls in particular, Guzi Jamjun [SP?], a graduate student from Saudi Arabia who trained at the Graduate School of Biomedical Science.Dr. Arlinghaus describes how Mr. Jamjun was able to help him in his own thinking about laboratory technique and methods, noting how rare it has been for him to find someone to discuss work deeply.At the end of the chapter, Dr. Arlinghaus gives advice to students and professionals: work hard, be honest, only publish what you believe.He also says that he doesn\u27t know how to instill drive and a sense of mission in people, but notes that if it\u27s a hobby, it\u27s not enough. He advises leaders to attract bright people and to listen to them.https://openworks.mdanderson.org/mchv_interviewchapters/1297/thumbnail.jp

Chapter 04: Leaving MD Anderson for Industry: Research into Hybrid Proteins with Tyrosine Kinase Activity

Dr. Arlinghaus explains that in 1983 he resigned from MD Anderson and took a job as Vaccine Development Director, Johnson and Johnson Biotechnology Center, in San Diego, California (1/1983-1/1986).They agreed to give him money to develop his CML research.He was able to secure his own laboratory space as a Visiting Investigator (Member) at the Scripps Clinic & Research Foundation in La Jolla (1/1983-1/1986).Dr. Arlinghaus describes his roles and notes that he arrived at Johnson and Johnson with an NCA grant awarded shortly before his departure from MD Anderson.Dr. Arlinghaus next describes the work he performed for Johnson and Johnson developing synthetic peptide vaccines.He describes the molecular chemistry that makes peptide vaccines impossible.He then outlines his next steps in studying the structure of the abnormal ABL protein in leukemia viruses.He describes the discovery of the ABL-fused gene in CML, adding a new dimension to his research and resulting in a 1995 paper.https://openworks.mdanderson.org/mchv_interviewchapters/1287/thumbnail.jp

Chapter 09: Fellowships and More Creative Research

In this chapter, Dr. Arlinghaus describes the research he conducted under the mentorship of Dr. Richard Schweet while he was on fellowship at the University of Kentucky College of Medicine, Lexington, Kentucky (1962-1963 and 1964 - 1965).Dr. Arlinghaus describes how he came to work on the mechanisms of peptide bond formation in ribosomes in hemoglobin.He describes the theory of this process at the time that long chains of proteins were assembled.Dr. Arlinghaus\u27s research revealed a different and more complex, two-stop mechanism involving ribosomes, messenger RNA and translocation processes.Dr. Arlinghaus notes that this ribosome mechanism is now in textbooks and, at the time, it won him national recognition.He recalls giving a talk in Atlantic City, noting that he wasn\u27t nervous, but confident because I knew what no one in this room knew and I was going to tell them about it. Dr. Arlinghaus states that he had knowledge and creativity and he reflects on where his abilities and research success came from: keeping up with the latest technique, luck, being simple minded, open minded, and aware that thing might be different than reported in textbooks.https://openworks.mdanderson.org/mchv_interviewchapters/1292/thumbnail.jp

Chapter 01: Key Research on ABL Kinases

Dr. Arlinghaus first talks about a study he will soon initiate on the role of JANUS Kinase 2 on chronic lymphocytic leukemia. He next quickly defines the field of molecular pathology and techniques that molecular pathologists use to break open cells and analyze their functions. He gives the example of the drug, Gleevec, and his contributions to work that unraveled how Gleevec successfully deactivates a key cell function that maintains leukemia. Next he talks about his work on the ABL kinase protein and chronic myeloid leukemia). He explains how this protein is involved in cell abnormalities and signaling functions that support the production of leukemia cells. He then goes into detail about how the BCR-ABL onco-proteins lead to leukemia. He notes some of the early studies that advanced knowledge, but did not immediately lead to treatment because the drugs under study (a precursor of Gleevec) were too toxic.https://openworks.mdanderson.org/mchv_interviewchapters/1284/thumbnail.jp

Chapter 05: Nursing in the Department of Developmental Therapeutics

In this chapter, Dr. Ecung provides a portrait of her work in the Department of Developmental Therapeutics when she returned to MD Anderson in 1978. She explains the physical organization of the clinic (Station 16). She discusses how she reorganized patients by disease type and assigned specific nurses to each disease type to deepen their knowledge so they might be more effective working with faculty and teaching patients about their diseases. She talks about the impact –notably in the retention of nurses. Next, Dr. Ecung talks about the working relationships between research nurses and clinical nurses in Developmental Therapeutics.https://openworks.mdanderson.org/mchv_interviewchapters/1690/thumbnail.jp